Contact dermatitis is responsible for over 5.6 million doctor visits each year in the United States and accounts for 15-20% of all occupational diseases. Including lost workdays and loss of productivity, the estimated total annual costs associated with occupational skin diseases approach $1 billion annually in the United States (CDC National Institute of Occupational Health, Update Jul. 1997) and up to $3 billion annually in Germany (Merk, Baron et al. 2006). Eighty percent of contact dermatitis instances are due to irritants while in the other 20% the compound induces an immunologic cascade and are classified as allergic (Leung, Diaz et al. 1997).
Contact dermatitis and many hypersensitivity reactions of the skin are produced by haptens, in the form of low molecular weight molecules or metal ions, complexing with cellular proteins. Subsequently these are processed into peptides and presented on the surface of antigen-presenting cells (APCs), typically Langerhans cells, the principle APC of the skin, residing in the epidermis (Saint-Mezard, Krasteva et al. 2003). Once Langerhans undergo maturation they migrate to the regional lymph node and present hapten-modified peptides in the context of major histocompatibility class I and II molecules to hapten-specific CD8+ and CD4+ T cells, respectively (Saint-Mezard, Berard et al. 2004). Antigen-specific activation of T cells constitutes the sensitization phase of contact sensitivity responses. Upon subsequent exposure to hapten, the challenge phase, effector memory T cells migrate to the peripheral tissues harboring hapten-presenting APCs. Here antigen recognition induces the T cells to express various mediators of inflammation and cytotoxicity, ultimately causing dermatitis and tissue damage (Saint-Mezard, Rosieres et al. 2004).
One of the anti-apoptotic proteins that is upregulated in T cells following T-cell activation is CFLAR (Kirchhoff, Muller et al. 2000). T cells that upregulate CFLAR as a consequence of T-cell receptor (TCR) engagement are resistant to Fas-mediated apoptosis. It has been clearly established that this CFLAR associated resistance correlates with de novo protein synthesis of CFLARS (Schmitz, Weyd et al. 2004). In these studies, it was also shown that CFLAR exerted its anti-apoptotic effect by blocking DISC activity. Increased expression of CFLAR is also seen following cross-linking of the B-cell receptor for antigen. In this case the upregulation was seen in the levels of CFLARL and was also associated with inhibition of Fas-mediated apoptosis (Wang, Lobito et al. 2000). CFLAR expression levels are also associated with the resistance to apoptosis that is seen following monocyte to macrophage differentiation (Perlman, Pagliari et al. 1999). It appears that CFLAR is commonly upregulated as a first step to prevent Fas-mediated apoptosis following signals for subsequent cell differentiation.
Although the signaling pathways associated with apoptosis and immunoregulation are complex and incompletely understood, CFLAR is one anti-apoptotic molecule that appears to play an important role in cell survival especially following death receptor ligation (Thorburn 2004).
A disclosure of antisense targeting of CFLAR, as shown in Mourich, et al (US20050203041 and WO2005030799), describes the use of such compounds to treat transplantation rejection and autoimmune conditions. The circulating T cells targeted by the methods and compositions of US20050203041 are activated by alloantigens that induce a graft versus host response in the case of transplantation and hyper-activated T cells responding to self antigens in the case of autoimmune conditions.
Accordingly, given the absence of a sufficient number of interventions for combating contact hypersensitivity, the present invention solves this deficiency while providing other related advantages.